Publication Date:
2012-08-14
Description:
Burkitt's lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein-Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609867/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmitz, Roland -- Young, Ryan M -- Ceribelli, Michele -- Jhavar, Sameer -- Xiao, Wenming -- Zhang, Meili -- Wright, George -- Shaffer, Arthur L -- Hodson, Daniel J -- Buras, Eric -- Liu, Xuelu -- Powell, John -- Yang, Yandan -- Xu, Weihong -- Zhao, Hong -- Kohlhammer, Holger -- Rosenwald, Andreas -- Kluin, Philip -- Muller-Hermelink, Hans Konrad -- Ott, German -- Gascoyne, Randy D -- Connors, Joseph M -- Rimsza, Lisa M -- Campo, Elias -- Jaffe, Elaine S -- Delabie, Jan -- Smeland, Erlend B -- Ogwang, Martin D -- Reynolds, Steven J -- Fisher, Richard I -- Braziel, Rita M -- Tubbs, Raymond R -- Cook, James R -- Weisenburger, Dennis D -- Chan, Wing C -- Pittaluga, Stefania -- Wilson, Wyndham -- Waldmann, Thomas A -- Rowe, Martin -- Mbulaiteye, Sam M -- Rickinson, Alan B -- Staudt, Louis M -- N01-CO-12400/CO/NCI NIH HHS/ -- U01-CA 114778/CA/NCI NIH HHS/ -- ZIA CP010176-11/Intramural NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Oct 4;490(7418):116-20. doi: 10.1038/nature11378. Epub 2012 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Metabolism Branch Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22885699" target="_blank"〉PubMed〈/a〉
Keywords:
Basic Helix-Loop-Helix Transcription Factors/antagonists &
;
inhibitors/genetics/metabolism
;
Burkitt Lymphoma/*drug therapy/*genetics/metabolism/pathology
;
Cell Cycle
;
Cyclin D3/genetics/metabolism
;
Cyclin-Dependent Kinase 6/metabolism
;
Genes, myc/genetics
;
*Genomics
;
High-Throughput Nucleotide Sequencing
;
Humans
;
Inhibitor of Differentiation Proteins/genetics/metabolism
;
*Molecular Targeted Therapy
;
Neoplasm Proteins/genetics/metabolism
;
Phosphatidylinositol 3-Kinases/metabolism
;
RNA Interference
;
Receptors, Antigen, B-Cell/metabolism
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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